Response to Interferon Beta-1a Treatment in African American Multiple Sclerosis Patients FREE

The disease course of multiple sclerosis (MS) for African American (AA) patients may be more severe than that of white Americans (WAs).¹ Therefore, it is possible that disease-modifying drugs or the disease course, as studied in clinical trials, may be responsible for different effects in AA compared with WA MS subjects. To test this hypothesis, a post hoc analysis comparing AA with WA response to treatment with interferon beta-1a was investigated using the Evidence of Interferon Dose-Response: European North American Comparative Efficacy (EVIDENCE) data set.² The EVIDENCE trial was a multicenter, randomized, assessor-blinded study comparing the efficacy of once weekly 30-μg interferon beta-1a (Avonex; Biogen Idec, Cambridge, Mass) with that of thrice weekly 44-μg interferon beta-1a (Rebif; Serono, Inc) on relapses and magnetic resonance imaging markers of disease activity during 48 weeks of therapy in previously untreated relapsing-remitting MS patients.

The patients (616 WAs and 36 AAs) were randomized to receive either 30 μg once weekly (AA;21 patients) or 44 μg thrice weekly (AA;15 patients) of interferon beta-1a in the EVIDENCE trial. Twenty-five patients with a non-WA, a non-AA, or an unspecified ethnicity were excluded from this subgroup analysis. The response to treatment was compared using ethnicity as a predictor. Statistical analysis was performed using SAS statistical software (SAS Institute Inc, Cary, NC) by Serono, Inc, biostatisticians. For baseline continuous variables, P values presented were calculated using the 2-sided Wilcoxon rank sum test. For baseline categorical variables, P values were calculated using the 2-sided Fisher exact test. An unadjusted comparison of mean values used the t test, and proportions were compared using the χ² test. Multiple regression modeling was used to adjust for confounding by baseline covariates: treatment (30 μg once weekly or 44 μg thrice weekly of interferon beta-1a), baseline Expanded Disability Status Scale score, baseline attack rate, baseline magnetic resonance imaging findings, and sex. Covariates that did not contribute significantly to the model were dropped. Interactions between covariates were tested for, but none were identified.

The baseline characteristics of AA and WA subjects were similar: 13.9% of AA and 25.5% of WA subjects were men (P = .16). The median age of onset was 32.1 years in AA subjects and 31.8 years in WA subjects (P = .87). The median disease duration was 5.6 years in AA subjects and 6.9 years in WA subjects (P = .14). The baseline median number of attacks in the 2 years before the study was 2.5 in AA subjects and 2.6 in WA subjects (P = .95). The baseline median number of combined unique lesions (active T2- and T1-weighted gadolinium–diethylene triamine pentaacetic acid–enhancing lesions) was 2.3 in AA subjects and 2.6 in WA subjects (P = .12). The baseline median Expanded Disability Status Scale score was 2.8 in AA subjects and 2.3 in WA subjects (P = .06). The ratio of treatment with either once weekly or thrice weekly interferon beta-1a was 23:13 for AA subjects and 303:313 for WA subjects (P = .12). In WA subjects, as in the entire EVIDENCE data set, there was a benefit of 3 times weekly subcutaneous interferon beta-1a compared with once-weekly intramuscular interferon beta-1a. Compared with WA subjects, AA subjects experienced more exacerbations (Figure 1) and were less likely to be exacerbation free (Figure 2) over the 24- and 48-week time frames. The AA subjects also had more combined unique T2-weighted and enhancing lesions at 24 weeks and more new T2-weighted lesions at 48 weeks (Figure 3). Statistical significance for differences in response to treatment was reached only in T2-weighted lesions at 48 weeks (Figure 3).

By using multivariate modeling adjusting for baseline variables, AA subjects had 0.55 times lesser odds of being relapse free than WA subjects at 48 weeks, adjusting for baseline relapse rate in the 2 years before the study and treatment effect (P = .10). The AA subjects had 0.31 more relapses (log scale) than the WA subjects at 48 weeks, adjusting for baseline relapse count and treatment effect (P = .21). The AA subjects had 0.96 more new T2-weighted lesions at 48 weeks than the WA subjects, adjusting for baseline T2-weighted lesions and treatment effect (P = .04). The AA subjects had lesser odds (odds ratio, 0.51) of having no new T2-weighted lesions at 48 weeks compared with the WA subjects, adjusting for baseline T2-weighted lesions and treatment (P = .09). Similar results were found for the 24-week outcome measures.

Despite the small sample size, AA subjects appeared less responsive to treatment than WA subjects on outcome measures, reaching significance only for the T2-weighted lesion count at 48 weeks. However, it is difficult to base these differences solely on response to treatment given the potential differing in MS disease course in AA patients. Indeed, there are several lines of reasoning that suggest that these observations may be valid. This trial was not designed to detect differences in treatment response between ethnic groups and, consequently, was underpowered for this analysis. Nevertheless, these results are suggestive and are of considerable potential importance. Statistically significant differences may have been observed on additional outcomes if more AA subjects had been included in the EVIDENCE study. The AA MS subjects seemed less responsive (trends) to interferon beta-1a for all measures, a finding that would be unanticipated if these observations were spurious. Interestingly, a similar differential response to treatment with interferon alfa-2b in AA compared with WA subjects is observed for the treatment of hepatitis C.³ It is plausible that genetic variation between AA and WA subjects could result in a different biological response to interferon. Further studies on the interaction between ethnicity and response to interferon treatment and other disease-modifying drugs for MS are warranted.

Correspondence: Bruce A. C. Cree, MD, PhD, MCR, Multiple Sclerosis Center, University of California, San Francisco, 350 Parnassus Ave, Suite 908, San Francisco, CA 94117 (bcree@itsa.ucsf.edu).

Accepted for Publication: July 6, 2005.

Author Contributions:Study concept and design: Cree and Goodin. Acquisition of data: Bennett. Analysis and interpretation of data: Cree, Al-Sabbagh, Bennett, and Goodin. Drafting of the manuscript: Cree. Critical revision of the manuscript for important intellectual content: Cree, Al-Sabbagh, Bennett, and Goodin. Statistical analysis: Cree, Al-Sabbagh, Bennett, and Goodin. Administrative, technical, and material support: Cree, Al-Sabbagh, Bennett, and Goodin. Study supervision: Goodin.

Financial Disclosure: Drs Cree and Goodin have received speaker honoraria from Biogen Idec and Serono, Inc.

Funding/Support: Dr Cree is a Sylvia Lawry fellow of the National Multiple Sclerosis Society, New York, NY.